Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

Abstract

Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.

Differential genetic diagnoses of adult post-lingual hearing loss according to the audiogram pattern and novel candidate gene evaluation

“…Various genetic studies on HL using panel sequencing and/ or ES previously evaluated clinical efficiency according to ethnicity, age of onset, or severity (Kim et al 2020;Shearer et al 2014;Yuan et al 2020). However, few studies have investigated the diagnostic rates of genetic testing in relation to audiogram patterns (Song et al 2020), which is the first-line diagnostic tool in HL evaluation.…”

A multiplex PCR amplicon sequencing assay to screen genetic hearing loss variants in newborns

“…Still, we covered all the hotspot variants in the Chinese population (Fig. 2 b), including c.919-2A>G, c.2168A>G, c.1975G>C, which accounts for 13.39% of the cases contributed to the SLC26A4 gene in a cohort of 864 Chinese patients [ 35 ].…”

Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

“…However, genetic variants responsible for a large number of cases of hereditary hearing loss remain unknown. Next-generation sequencing has greatly increased the efficiency in screening known deafness genes for diagnostic purposes and in identifying new deafness genes [ 37 – 40 ].…”